The invention relates to photodynamic therapy.
Photodynamic therapy (PDT) was first developed as an experimental treatment for cancer. The treatment was based on the observation that cancer cells could retain photoactivatable compounds and could be selectively killed when these compounds subsequently interacted with absorbed light (see e.g., Bottiroli et al., Photochem. Photobiol. 47:209-214, 1988; Salet et al., Photochem. Photobiol. 53:391-393, 1991; Gross, In Photobiological Techniques, Valenzeno et al. Eds., Plenum Press, New York, 1991; and Jori et al., In Photodynamic Therapy of Neoplastic Disease, Kessel Ed., CRC Press, Boca Raton, Fla., 1989). A photodynamic compound that is widely used is marketed as Photofrin.RTM.. Photofrin.RTM./HPD (hematoporphyrin derivative) was the first FDA approved photosensitizing agent available for PDT trials. Photofrin.RTM. has subsequently been tested extensively for the destruction of multiple tumors in numerous medical disciplines (Dougherty et al., In Photodynamic Therapy of Neoplastic Disease, Kessel Ed., supra).
The mechanism of action for hematoporphyrin derivatives such as Photofrin.RTM. in the treatment of neoplastic disease is well delineated. Large molecular aggregates of the porphyrins accumulate around tumor neovasculature. This accumulation is caused by poor lymphatic drainage from the neoplastic tissues. Once sequestered in the tissue, the molecular aggregates dissociate, and the hydrophobic components of the porphyrin cause it to partition into cell membranes, primarily into the cellular and mitochondrial membranes.
Initiation of photodynamic activity is caused by excitation of the photodynamic compound by light that falls within its absorption band. The wavelength specificity depends on the molecular structure of the photodynamic compound; a greater degree of conjugation within a molecule leads to greater absorbance at longer wavelengths. Activation of photodynamic compounds occurs with subablative light fluences. Toxicity is achieved by O.sub.2 radical toxicity. The singlet O.sub.2 reacts with, for example, double bonds to produce reactive species, for example, organoperoxides. These, in turn, initiate free radical chain reactions which degrade and disorganize membranes, uncouple oxidative phosphorylation, and lead to cellular disruption (Jori et al., supra; Weishaupt et al., Cancer Res 36:2326-2329, 1976). Nucleic acids and proteins are also damaged by photooxidation (Henderson et al., In Porphyrin Localization and Treatment of Tumors, Doiron et al. Eds., Liss, N.Y., 1984).
Studies demonstrating destruction of synovium without significant side effects indicate that photochemical synovectomy is an effective treatment for rheumatoid arthritis (U.S. Pat. No. 5,368,841).